Related Experiment Videos
Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice
Ken-Ichiro Ishii1, Yoshiya Ito, Hiroyuki Katagiri
1Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Abstract:
The present study was conducted to elucidate the role of neutrophil elastase in lipopolysaccharide (LPS)-induced hepatic microvascular injury by using in vivo microscopy. The intravenous (i.v.) injection of LPS (0.1 mg/kg) in male C3H/HeN mice caused significant hepatic microcirculatory dysfunction: leukocyte adhesion to the sinusoids as well as to the venule, and reduced sinusoidal perfusion, in comparison with vehicle-treated mice. Concomitantly, the serum alanine aminotransferase (ALT) activity at 4 h after LPS injection was significantly increased. The serum concentrations of tumor necrosis factor (TNFalpha) and interleukin-1beta (IL-1beta) at 1 h and at 4 h after LPS injection, respectively, were significantly elevated. Neutrophil elastase inhibitors, ONO-5046 (30 and 90 mg/kg, i.v., 0 and 2 h after LPS injection) or FK706 (30 and 100 mg/kg, i.v., 0 and 2 h after LPS injection) minimized the LPS-induced hepatic microcirculatory dysfunction in a dose-dependent manner. Treatment with ONO-5046 and FK706 significantly reduced the ALT level as well as the serum concentrations of TNFalpha and IL-1beta. In addition, ONO-5046 and FK706 attenuated both hepatic microcirculatory dysfunction and liver injury mediated by TNFalpha and IL-1beta (10 microg/kg i.v.). Furthermore, both ONO-5046 and FK706 improved human neutrophil elastase (10 microg/kg i.v.)-induced hepatic microcirculatory dysfunction, although neutrophil elastase did not increase the levels of TNFalpha and IL-1beta. These results suggest that neutrophil elastase aggravates the LPS-induced hepatic microvascular dysfunction. Neutrophil elastase inhibitors attenuate hepatic microvascular dysfunction in response to LPS by inhibiting TNFalpha and IL-1beta production. Neutrophil elastase inhibitors also reduce the microvascular dysfunction mediated by TNFalpha and IL-1beta as well as by neutrophil elastase.
Insights
Neutrophil elastase worsens liver injury caused by lipopolysaccharide (LPS). Inhibiting neutrophil elastase reduces this LPS-induced hepatic microvascular dysfunction and liver damage by lowering inflammatory cytokines.
Area of Science:
- Hepatology
- Immunology
- Microcirculation Research
Background:
- Lipopolysaccharide (LPS) triggers hepatic microvascular injury.
- Neutrophil elastase (NE) is implicated in inflammatory responses.
- Understanding NE's role in LPS-induced liver injury is crucial.
Purpose of the Study:
- To investigate the role of neutrophil elastase in lipopolysaccharide (LPS)-induced hepatic microvascular injury.
- To evaluate the efficacy of neutrophil elastase inhibitors in mitigating LPS-induced liver damage.
Main Methods:
- In vivo microscopy was used to assess hepatic microcirculation in mice.
- LPS was administered intravenously to induce liver injury.
- Neutrophil elastase inhibitors (ONO-5046, FK706) were administered to evaluate their protective effects.
Main Results:
- LPS injection caused significant hepatic microcirculatory dysfunction, increased alanine aminotransferase (ALT) levels, and elevated pro-inflammatory cytokines (TNF-alpha, IL-1beta).
- Neutrophil elastase inhibitors dose-dependently attenuated LPS-induced microcirculatory dysfunction and liver injury.
- Inhibitors reduced ALT levels and suppressed TNF-alpha and IL-1beta production, also mitigating injury mediated by these cytokines and by NE itself.
Conclusions:
- Neutrophil elastase exacerbates LPS-induced hepatic microvascular dysfunction.
- Neutrophil elastase inhibitors offer a therapeutic strategy by reducing inflammatory cytokine production and mitigating microvascular injury in the liver.
- Targeting neutrophil elastase is a promising approach for managing LPS-induced liver injury.